Immunology Graduate Group
Craig Thompson, M.D.
Address: 451 Biomedical Research Bldg (BRB) II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office Phone: (215) 746-5515
Lab Phone: (215) 746-5527
Fax: (215) 746-5511
Email: craig@mail.med.upenn.edu
Education:
A.D., Dartmouth College
M.D., University of Pennsylvania
Research Interests
Regulation of lymphocyte development, proliferation, survival, and transformation.
Key words: Apoptosis, carcinogenesis, immunology, signal transduction.
Research Summary
The Thompson laboratory's research effort focuses on investigating the hypothesis that metazoan cell growth is limited by the inability of cells to take up sufficient nutrients to maintain either replacement biosynthesis or cell survival. This hypothesis was formulated to explain how multicellularity might have arisen and been selected for during evolution. An important corollary of this hypothesis is that the lack of a cell intrinsic mechanism to regulate nutrient uptake limits the ability of cells to proliferate in a cell-autonomous fashion. In addition, we believe that this hypothesis has important implications to the regulation of cell size and number. The laboratory focuses on the study of immune cells as a model system to investigate this hypothesis, extending studies to other cell types where appropriate.
Genetic Control of Apoptosis.
The hypothesis has arisen out of our work to characterize the molecular basis by which Bcl-2 proteins regulate cell survival. Our working model for the biochemical function of Bcl-2 proteins is that they are critical regulators of metabolite and ion exchange between intracellular organelles and the cytoplasm. In the last year we have confirmed parts of this model by demonstrating that Bcl-2 proteins play a critical role in regulating metabolite exchange across mitochondrial outer membrane and calcium homeostasis across the endoplasmic reticulum. In addition, we have established that Bcl-2 regulates the initiation of apoptosis not only from mitochondria but also from the endoplasmic reticulum. Based on this work, we continue to believe that Bcl-2 proteins regulate the efficiency with which cellular bioenergetics is coupled and therefore prolong the interval in which an individual cell can live in the absence of exogenous signals required for nutrient uptake. To further substantiate this hypothesis, we have established immortalized 3T3 equivalent and IL-3-dependent cell lines that lack the ability to carry out apoptosis through the Bcl-2 pathway and are characterizing the regulation of cellular bioenergetics in the presence and absence of either serum or growth factors.
Based on our model, we have begun to explore whether the molecular signaling pathways that regulate nutrient uptake promote cell survival. In addition, we have branched out to consider the regulation of essential nutrients beyond glucose by examining amino acid transporter expression. Based on this work, we have been able to find two independent and parallel pathways that regulate nutrient uptake and thus promote cell survival. The first of these is defined by the PI3K/AKT/PTEN/mTOR pathway. We have extended our observations in this area by demonstrating that, as in yeast, mTOR is a critical regulator of amino acid uptake and transporter function. We have demonstrated that mutations that limit processing of glucose and amino acid transporters from the cell surface in response to either growth factor withdrawal or TOR inhibition can lead to prolonged cell autonomous survival. In addition, we have demonstrated that constitutively active forms of mTOR render cells resistant to apoptosis induction.
Progress has also been made in identifying an alternative pathway for the regulation of nutrient uptake. The existence of this pathway was established initially by demonstrating that rapamycin, an inhibitor of mTOR, or PI3K inhibitors were not effective at limiting nutrient uptake by cells in the presence of growth factor. This alternative pathway has been established to be regulated in IL-3-dependent cells by Jack3/Stat5/Pim-2. The demonstration of the existence of such a pathway was first demonstrated in cell lines and had now been confirmed using knockout mice. In addition, several additional components in the signaling pathway have begun to become clarified. These include the serine/threonine kinase COT which activates NFkB, and translational regulator protein 4E-BP1. Studies are underway to exploit the fact that each of the components so far established on this pathway are oncogenes.
Studies of T Cell Activation: the contribution of bioenergetic control to T cell immune response.
Based on our published work suggesting that costimulation regulates lymphocyte nutrient uptake and is required for lymphocytes to match resource acquisition to the biologic demands of cell proliferation, we have begun to examine the role of evolutionary conserved nutrient sensing pathways in T cell biology. Two areas where we have made considerable progress are in the regulation of T cell activation by AMPK and the regulation of T cell survival by the TOR substrate a4. While our data allow us to establish that these two regulators of serine phosphorylation are critical regulators of immune activation, the molecular events by which they mediate these effects remain to be determined and are under active investigation.
Bioenergetics and Cell Growth.
Based on our interests in the synthetic and bioenergetic requirements of cell proliferation and how a cell meets these demands, we now have developed an active program in studying the bioenergetics of cell proliferation. Growing cells require high quantities of NADPH, acetyl CoA, S-adenosyl methionine, and pentenyl pyrophosphate, all of which are direct byproducts of mitochondrial bioenergetics and can be produced only when pyruvate is in vast excess of that needed to produce sufficient NADH to maintain NADP production. This work has suggested to us that agents involved in inhibiting the production of these precursor molecules may play an important role as anti-neoplastic agents. In the last year we have begun to define how cytosolic acetyl-CoA is generated and how inhibitors of its production have important anti-neoplastic roles. This has allowed us the identification of a potentially novel anti-neoplastic agent and in vivo studies of inhibitors of this pathway are ongoing as a result of a collaboration with GSK. We believe these studies represent a potentially important validation of our approach to understanding cell growth and proliferation through studying bioenergetics.
Much of the work summarized above is under active investigation in the laboratory and as yet has not been reduced to publication. However, in the last year the laboratory has published 17 peer-reviewed and 5 non-peer reviewed articles and provide the evidence from which we have formulated our new area of research. These publications are listed below.
Recent Publications
Frauwirth, K.A., Riley, J.L., Harris, M.H., Parry, R.V., Rathmell, J.C., Plas, D.R., Elstrom, R.L., June, C.H., and Thompson, C.B. The CD28 signaling pathway regulates glucose metabolism. Immunity, 16:769-777, 2002.
Li, C. and Thompson, C.B. DNA damage, deamidation, and death. Science, 298:1346-1347, 2002.
Plas, D., and Thompson, C.B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J. Biol. Chem., 278:12361-12366, 2003.
Zong, W.-X., Li, C., Hatzivassiliou, G., Lindsten, T., Yu, Q.-C., Yuan, J., and Thompson, C.B. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J. Cell Biol., 162:59-69, 2003.
Fox, C.J., Hammerman, P.S., Cinalli, R.M., Master, S.R., Chodosh, L.A., and Thompson, C.B. The serine/threonine kinase Pim-2 is a transcriptionally-regulated apoptotic inhibitor. Genes & Dev., 17:1841-1854, 2003.
Lab personnel:
Daniel Bauer, Ph.D. (Graduate Student)
Monica Buzzai, B.S. (Graduate Student)
Ryan Cinalli (Research Technician)
Dara Ditsworth, B.S. (Graduate Student)
Aimee Edinger, Ph.D. (Postdoctoral Fellow)
Rebecca Elstrom, M.D. (Postdoctoral Fellow)
Kenneth Frauwirth, Ph.D. (Postdoctoral Fellow)
Casey Fox, Ph.D. (Postdoctoral Fellow)
Peter Hammerman, B.S.(Graduate Student)
Georgia Hatzivassiliou, Ph.D. (Postdoctoral Fellow)
Rusty Jones, Ph.D. (Postdoctoral Fellow)
Mei Kong, Ph.D. (Postdoctoral Fellow)
Sara Kubek, B.S. (Research Technician)
Chi Li, Ph.D. (Postdoctoral Fellow)
Tullia Lindsten, M.D., Ph.D. (Research Assistant Professor)
Julian Lum, Ph.D. (Postdoctoral Fellow)
David Plas, Ph.D. (Postdoctoral Fellow)
Laura Solt, B.S. (Graduate Student)
Anne Xu (Research Technician)
Wei-Xing Zong, Ph.D. (Postdoctoral Fellow)
Biomedical Graduate Studies | University of Pennsylvania | Contact